The impact of preadmission/prediagnosis use of GLP‐1 receptor agonists on COVID‐19 mortality in patients with diabetes: A systematic review and meta‐analysis

clinicians must exercise caution and carefully weigh the potential risks, particularly in patients with a predisposition to gatrointestinal issues and renal complications.


| Study selection
The literature screening process was conducted independently by two investigators (CSK and SSH) to identify eligible studies.The inclusion criteria for this systematic review were limited to observational studies that provided information on the risk of COVID-19-associated mortality in patients who had used GLP-1 receptor agonists before COVID-19 hospital admission or diagnosis, compared to those who had not used them.These studies were required to report adjusted mortality estimates in the form of odds ratio, hazard ratio, or relative risk, along with their corresponding 95% confidence intervals.
Excluded from consideration were studies that reported nonadjusted mortality estimates, as well as comments, case reports, conference papers, animal experiments, letters, and review articles that lacked original data.

| Study outcome
The primary outcome of interest was COVID-19-associated mortality.

| Data extraction
Data extraction was carried out by two investigators (CSK and DSR), who extracted important characteristics from each study.In cases where there were disagreements in the data extraction process, the investigators resolved them through discussion and consensus.

| Risk of bias assessment
The methodological quality of the observational studies included in the review was evaluated using the Newcastle-Ottawa Scale.This scale categorized the studies as low, moderate, or high quality based on assigned scores of 0-5, 6-7, and 8-9, respectively.The assessment of study quality was conducted independently by two investigators (CSK and SSH), who resolved any conflicts through discussion and consensus.

| Statistical analysis
The meta-analysis was conducted using the random-effects model to estimate the pooled odds ratio of mortality in COVID-19 patients who received GLP-1 receptor agonists before admission or diagnosis compared to those who did not.The analysis provided 95% confidence intervals to assess the precision of the findings.Heterogeneity among the included studies was evaluated using I 2 statistics and the χ 2 test, with significant heterogeneity defined as I 2 > 50% and a p < 0.10, respectively.All statistical computations were performed using Meta XL, version 5.3 (EpiGear International, Queensland, Australia).
The meta-analysis of the nine studies [9][10][11][12][13][14][15][16][17]  MasR axis. 18Indeed, animal models of lung injury have shown that GLP-1 receptor agonists can mitigate pulmonary inflammation, reduce cytokine production, and preserve lung function. 19Besides, GLP-1 receptor agonists can exert a favorable influence on gut microbiome composition by enriching Bacteroidetes, which is involved in lipopolysaccharide biosynthesis.This effect may play a role in averting the activation of proinflammatory pathways (such as Toll-Like Receptor 4-Nuclear Factor Kappa B) due to endotoxemia. 20In addition, GLP-1 receptor agonists can prevent or reduce the sustained hyperglycemia resulting from systemic inflammation related to COVID-19. 21vertheless, the use of GLP-1 receptor agonists is not without risks; GLP-1-based therapies have been notoriously linked to gastrointestinal side effects, including nausea, vomiting, and diarrhea, which may complicate gastrointestinal symptoms in patients with COVID-19. 22In addition, the use of GLP-1 receptor agonists have been infrequently associated with the development of acute kidney injury, particularly in patients with severe gastrointestinal adverse effects.The development of acute kidney injury in patients with COVID-19 has been associated with an increased risk of mortality. 23nsequently, while the potential benefits of GLP-  and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Chia Siang Kow 1
Dinesh Sangarran Ramachandram 2 Syed Shahzad Hasan 3,4 revealed significant reduction in the odds of mortality with preadmission/prediagnosis use of GLP-1 receptor agonists relative to non-use of GLP-1 receptor agonists in COVID-19 patients with diabetes.The combined analysis of the included studies (Figure 2) shows a pooled odds ratio of 0.83 (95% confidence interval: 0.72-0.97),indicating a beneficial effect of GLP-1 receptor agonists on mortality.4 | DISCUSSION To our knowledge, this systematic review and meta-analysis is the first to comprehensively summarize observational studies that have adjusted for covariates and examined the association between the use of GLP-1 receptor agonists before admission or diagnosis and the risk of mortality in patients with COVID-19 and diabetes.Our findings revealed significant mortality benefits with the preadmission use of GLP-1 receptor agonists, which should encourage further investigations through randomized controlled trials.Some researchers have discussed the potential repurposing of GLP-1 receptor agonists for the treatment of COVID-19, citing their ability to exert a pulmonary protective effect by stimulating the angiotensin-converting enzyme 2 (ACE2)/Angiotensin (1-7)/

5 |
CONCLUSION While the positive findings with the use of GLP-1 receptor agonists in patients with COVID-19 and concurrent diabetes are encouraging, clinicians are recommended not to prescribe GLP-1 receptor agonists solely for the purpose of improving the prognosis of this population of patients before the publication of more solid evidence from randomized controlled trials.Nonetheless, prescribing GLP-1 receptor agonists amid the COVID-19 pandemic should not be discouraged, as they can provide both cardioprotective and renoprotective benefits in patients with type 2 diabetes. 24,25KEYWORDS dulaglutide, liraglutide, lixisenatide, SARS-CoV-2, semaglutide AUTHOR CONTRIBUTIONS Chia Siang Kow: Conceptualization; Writing-original draft; Writingreview & editing.Dinesh Sangarran Ramachandram: Conceptualization; Writing-review & editing.Syed Shahzad Hasan: Writingoriginal draft; Writing-review & editing.ACKNOWLEDGMENTS Open access publishing facilitated by Monash University, as part of the Wiley -Monash University agreement via the Council of Australian University Librarians.
Characteristic of included studies.